Clinical Infectious Diseases Advance Access published March 18, 2014
1 Effect of Vancomycin Minimal Inhibitory Concentration on the Outcome of
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Methicillin-Susceptible Staphylococcus aureus Endocarditis
Carlos Cervera1, Ximena Castañeda1, Cristina Garcia de la Maria2, Ana del Rio1, Asunción Moreno1, Dolors Soy3, Juan Manuel Pericas1, Carlos
Falces4, Yolanda Armero2, Manel Almela5, Salvador Ninot6, Juan Carlos
us
and the Hospital Clinic Endocarditis Study Group7
Infectious Diseases Service, Hospital Clinic – IDIBAPS, University of
Barcelona, Barcelona, Spain 2
an
1
Experimental Endocarditis Research Laboratory, Hospital Clinic – IDIBAPS,
3
M
University of Barcelona, Barcelona, Spain
Pharmacy Service, Hospital Clinic – IDIBAPS, University of Barcelona,
4
pt ed
Barcelona, Spain
Cardiology Service,Hospital Clinic – IDIBAPS, University of Barcelona,
Barcelona, Spain 5
Microbiology Service, Hospital Clinic – IDIBAPS, University of Barcelona,
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Barcelona, Spain
6
Department of Cardiovascular surgery, Hospital Clinic – IDIBAPS, University of
Ac
Barcelona, Barcelona, Spain Corresponding author: Dr. Jose M. Miro, Infectious Diseases Service, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain ([email protected]).
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
Pare4, Carlos A. Mestres6, Jose M. Gatell1, Francesc Marco5, Jose M. Miro1,
2 7
Members of the Hospital Clinic Endocarditis Study Group are listed in the
Appendix.
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Alternative corresponding author: Dr. Carlos Cervera, Infectious Diseases Service, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain ([email protected]).
us
collected cohort of 93 patients with left-sided endocarditis caused by methicillin-
an
susceptible S. aureus treated with cloxacillin, in-hospital mortality was 3-fold higher in patients with endocarditis caused by strains with a vancomycin MIC ≥
Abstract
M
1.5 μg/mL.
pt ed
Background: Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus (MRSA) bacteremia, and recent data point to a similar effect on MSSA bacteremia. We aimed to evaluate the
ce
effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin.
Ac
Methods: We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (< 1.5 μg/mL) and high vancomycin MIC (≥ 1.5 μg/mL). The primary
endpoint was in-hospital mortality.
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
Brief comment on the article: In this retrospective analysis of a prospectively
3 Results: We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC < 1.5 μg/mL and 40 (43%) a
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vancomycin MIC ≥ 1.5 μg/mL. In-hospital mortality was 30% (16/53) in patients with a low vancomycin MIC and 53% (21/40) in those with a high vancomycin MIC (p=0.030). No correlation was found between oxacillin MIC and
vancomycin or daptomycin MIC. Logistic regression analysis showed that
non-septic complicated endocarditis.
us
1.2-8.2) after adjustment for age, year of diagnosis, septic complications, and
an
Conclusion: Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher
M
mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of
Ac
ce
pt ed
antibiotics.
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
higher vancomycin MIC increased in-hospital mortality 3-fold (OR 3.1, 95% CI
4 Introduction Staphylococcus aureus is the leading cause of infective endocarditis
cr ipt
worldwide.1 Native-valve S. aureus endocarditis is more frequently caused by methicillin-susceptible strains (MSSA) (85% of cases vs 15% in endocarditis caused by MRSA), leading to a higher incidence of embolic events, reduced need for surgery, and higher mortality than non-S. aureus native valve
us
medical management, the in-hospital mortality of MSSA endocarditis has remained unchanged at around 25% in recent decades.2,3
an
In the last few years, several investigations have addressed the issue of the high mortality associated with methicillin-resistant S. aureus (MRSA)
M
bacteremia. A higher vancomycin minimum inhibitory concentration (MIC) has been shown to confer a worse prognosis for MRSA bacteremia. 4-6 The results of the only study to analyze the effect of vancomycin MIC on the outcome of
pt ed
MRSA endocarditis7 revealed more frequent persistent bacteremia and a higher incidence of heart failure and mortality when the vancomycin MIC was higher than 1.5 mg/L; however, the sample size was too small to draw firm conclusions.
ce
A strong association between vancomycin MIC and the outcome of MSSA bacteremia was recently reported, regardless of the antibiotic treatment
Ac
administered (anti-staphylococcal penicillin or vancomycin).8,9 The study by Holmes et al.8 revealed that mortality increased 2.4-fold in patients with a
vancomycin MIC >1.5 mg/L. In addition, the choice of antibiotic (vancomycin or betalactam) for the treatment of S. aureus bacteremia had no statistically
significant effect on 30-day mortality in the multivariate model.8 Moreover, in
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
endocarditis.2 Despite considerable advances in diagnosis and surgical and
5 another manuscript by the same authors, vancomycin MIC was an independent risk factor for 30-day mortality of MSSA bacteremia after adjustment for
cr ipt
comorbidities and disease severity.10 This finding is very relevant, as it demonstrates that higher vancomycin MIC is a prognostic factor for mortality in S. aureus bacteremia, regardless of resistance to methicillin or the treatment administered. However, the pathophysiologic mechanisms underlying this
us
lacking.
The aim of this study was to analyze whether the MIC of vancomycin
M
Methods
an
could be a prognostic marker in cloxacillin-treated left-sided MSSA endocarditis.
We designed a retrospective analysis of a prospectively collected cohort in
pt ed
Hospital Clínic of Barcelona, an 800-bed tertiary-care teaching center in Spain. All consecutive cases of infective endocarditis (IE) diagnosed from 1995 to 2011 at our center were collected in a case report form and a prospective database. The variables recorded included demographics, characteristics of the
ce
IE episode, complications, treatment, and outcome. All patients who survived were followed for at least 1 year. All cases of MSSA endocarditis were treated
with intravenous cloxacillin (2 g/4 h) according to American Heart Association
Ac
guidelines.11 We included only patients with confirmed endocarditis. Throughout the study period, the senior team in charge of patients with endocarditis remained unchanged (AM, MA, SN, JCP, CAM, JMG, FM, and JMM). We included only patients with confirmed endocarditis.
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
finding remain unknown, and data for patients with MSSA endocarditis are
6
Definitions: The diagnosis of confirmed endocarditis was based on the
cr ipt
modified Duke criteria.12 Septic complicated endocarditis was defined as endocarditis with severe sepsis or septic shock at diagnosis, both defined
following the International Sepsis Definitions Conference.13 We defined non-
septic complicated endocarditis as endocarditis with 1 or more of the following
us
at baseline or during the first 2 weeks of follow-up.
an
Vancomycin MIC determinations: S. aureus strains were collected and stored at –80ºC. The selected isolates were thawed and used to determine the MICs of
France).
M
oxacillin, vancomycin, and daptomycin (E-test, bioMérieux, Marcy l'Etoile,
pt ed
Primary endpoint: The primary endpoint was in-hospital survival. One-year survival was analyzed as a secondary endpoint.
Statistical analysis: Categorical variables are expressed as a percentage and
ce
were compared using the chi-square or Fisher exact test. Continuous variables are expressed as means or medians (depending on homogeneity) and were compared using the t test or Mann-Whitney test. Survival was analyzed using
Ac
the Kaplan-Meier method. Plots were compared using the log-rank test. Correlations were calculated using Spearman’s rho test. We used backward stepwise logistic regression analysis to identify independent variables associated with 1-year mortality and included those variables with p
1 Effect of Vancomycin Minimal Inhibitory Concentration on the Outcome of
cr ipt
Methicillin-Susceptible Staphylococcus aureus Endocarditis
Carlos Cervera1, Ximena Castañeda1, Cristina Garcia de la Maria2, Ana del Rio1, Asunción Moreno1, Dolors Soy3, Juan Manuel Pericas1, Carlos
Falces4, Yolanda Armero2, Manel Almela5, Salvador Ninot6, Juan Carlos
us
and the Hospital Clinic Endocarditis Study Group7
Infectious Diseases Service, Hospital Clinic – IDIBAPS, University of
Barcelona, Barcelona, Spain 2
an
1
Experimental Endocarditis Research Laboratory, Hospital Clinic – IDIBAPS,
3
M
University of Barcelona, Barcelona, Spain
Pharmacy Service, Hospital Clinic – IDIBAPS, University of Barcelona,
4
pt ed
Barcelona, Spain
Cardiology Service,Hospital Clinic – IDIBAPS, University of Barcelona,
Barcelona, Spain 5
Microbiology Service, Hospital Clinic – IDIBAPS, University of Barcelona,
ce
Barcelona, Spain
6
Department of Cardiovascular surgery, Hospital Clinic – IDIBAPS, University of
Ac
Barcelona, Barcelona, Spain Corresponding author: Dr. Jose M. Miro, Infectious Diseases Service, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain ([email protected]).
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
Pare4, Carlos A. Mestres6, Jose M. Gatell1, Francesc Marco5, Jose M. Miro1,
2 7
Members of the Hospital Clinic Endocarditis Study Group are listed in the
Appendix.
cr ipt
Alternative corresponding author: Dr. Carlos Cervera, Infectious Diseases Service, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain ([email protected]).
us
collected cohort of 93 patients with left-sided endocarditis caused by methicillin-
an
susceptible S. aureus treated with cloxacillin, in-hospital mortality was 3-fold higher in patients with endocarditis caused by strains with a vancomycin MIC ≥
Abstract
M
1.5 μg/mL.
pt ed
Background: Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus (MRSA) bacteremia, and recent data point to a similar effect on MSSA bacteremia. We aimed to evaluate the
ce
effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin.
Ac
Methods: We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (< 1.5 μg/mL) and high vancomycin MIC (≥ 1.5 μg/mL). The primary
endpoint was in-hospital mortality.
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
Brief comment on the article: In this retrospective analysis of a prospectively
3 Results: We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC < 1.5 μg/mL and 40 (43%) a
cr ipt
vancomycin MIC ≥ 1.5 μg/mL. In-hospital mortality was 30% (16/53) in patients with a low vancomycin MIC and 53% (21/40) in those with a high vancomycin MIC (p=0.030). No correlation was found between oxacillin MIC and
vancomycin or daptomycin MIC. Logistic regression analysis showed that
non-septic complicated endocarditis.
us
1.2-8.2) after adjustment for age, year of diagnosis, septic complications, and
an
Conclusion: Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher
M
mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of
Ac
ce
pt ed
antibiotics.
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
higher vancomycin MIC increased in-hospital mortality 3-fold (OR 3.1, 95% CI
4 Introduction Staphylococcus aureus is the leading cause of infective endocarditis
cr ipt
worldwide.1 Native-valve S. aureus endocarditis is more frequently caused by methicillin-susceptible strains (MSSA) (85% of cases vs 15% in endocarditis caused by MRSA), leading to a higher incidence of embolic events, reduced need for surgery, and higher mortality than non-S. aureus native valve
us
medical management, the in-hospital mortality of MSSA endocarditis has remained unchanged at around 25% in recent decades.2,3
an
In the last few years, several investigations have addressed the issue of the high mortality associated with methicillin-resistant S. aureus (MRSA)
M
bacteremia. A higher vancomycin minimum inhibitory concentration (MIC) has been shown to confer a worse prognosis for MRSA bacteremia. 4-6 The results of the only study to analyze the effect of vancomycin MIC on the outcome of
pt ed
MRSA endocarditis7 revealed more frequent persistent bacteremia and a higher incidence of heart failure and mortality when the vancomycin MIC was higher than 1.5 mg/L; however, the sample size was too small to draw firm conclusions.
ce
A strong association between vancomycin MIC and the outcome of MSSA bacteremia was recently reported, regardless of the antibiotic treatment
Ac
administered (anti-staphylococcal penicillin or vancomycin).8,9 The study by Holmes et al.8 revealed that mortality increased 2.4-fold in patients with a
vancomycin MIC >1.5 mg/L. In addition, the choice of antibiotic (vancomycin or betalactam) for the treatment of S. aureus bacteremia had no statistically
significant effect on 30-day mortality in the multivariate model.8 Moreover, in
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
endocarditis.2 Despite considerable advances in diagnosis and surgical and
5 another manuscript by the same authors, vancomycin MIC was an independent risk factor for 30-day mortality of MSSA bacteremia after adjustment for
cr ipt
comorbidities and disease severity.10 This finding is very relevant, as it demonstrates that higher vancomycin MIC is a prognostic factor for mortality in S. aureus bacteremia, regardless of resistance to methicillin or the treatment administered. However, the pathophysiologic mechanisms underlying this
us
lacking.
The aim of this study was to analyze whether the MIC of vancomycin
M
Methods
an
could be a prognostic marker in cloxacillin-treated left-sided MSSA endocarditis.
We designed a retrospective analysis of a prospectively collected cohort in
pt ed
Hospital Clínic of Barcelona, an 800-bed tertiary-care teaching center in Spain. All consecutive cases of infective endocarditis (IE) diagnosed from 1995 to 2011 at our center were collected in a case report form and a prospective database. The variables recorded included demographics, characteristics of the
ce
IE episode, complications, treatment, and outcome. All patients who survived were followed for at least 1 year. All cases of MSSA endocarditis were treated
with intravenous cloxacillin (2 g/4 h) according to American Heart Association
Ac
guidelines.11 We included only patients with confirmed endocarditis. Throughout the study period, the senior team in charge of patients with endocarditis remained unchanged (AM, MA, SN, JCP, CAM, JMG, FM, and JMM). We included only patients with confirmed endocarditis.
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on April 6, 2014
finding remain unknown, and data for patients with MSSA endocarditis are
6
Definitions: The diagnosis of confirmed endocarditis was based on the
cr ipt
modified Duke criteria.12 Septic complicated endocarditis was defined as endocarditis with severe sepsis or septic shock at diagnosis, both defined
following the International Sepsis Definitions Conference.13 We defined non-
septic complicated endocarditis as endocarditis with 1 or more of the following
us
at baseline or during the first 2 weeks of follow-up.
an
Vancomycin MIC determinations: S. aureus strains were collected and stored at –80ºC. The selected isolates were thawed and used to determine the MICs of
France).
M
oxacillin, vancomycin, and daptomycin (E-test, bioMérieux, Marcy l'Etoile,
pt ed
Primary endpoint: The primary endpoint was in-hospital survival. One-year survival was analyzed as a secondary endpoint.
Statistical analysis: Categorical variables are expressed as a percentage and
ce
were compared using the chi-square or Fisher exact test. Continuous variables are expressed as means or medians (depending on homogeneity) and were compared using the t test or Mann-Whitney test. Survival was analyzed using
Ac
the Kaplan-Meier method. Plots were compared using the log-rank test. Correlations were calculated using Spearman’s rho test. We used backward stepwise logistic regression analysis to identify independent variables associated with 1-year mortality and included those variables with p
